US11156684B2 - Method for creating hyperpolarization at microTesla magnetic fields - Google Patents
Method for creating hyperpolarization at microTesla magnetic fields Download PDFInfo
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- US11156684B2 US11156684B2 US14/925,507 US201514925507A US11156684B2 US 11156684 B2 US11156684 B2 US 11156684B2 US 201514925507 A US201514925507 A US 201514925507A US 11156684 B2 US11156684 B2 US 11156684B2
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
- G01R33/445—MR involving a non-standard magnetic field B0, e.g. of low magnitude as in the earth's magnetic field or in nanoTesla spectroscopy, comprising a polarizing magnetic field for pre-polarisation, B0 with a temporal variation of its magnitude or direction such as field cycling of B0 or rotation of the direction of B0, or spatially inhomogeneous B0 like in fringe-field MR or in stray-field imaging
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
- G01R33/282—Means specially adapted for hyperpolarisation or for hyperpolarised contrast agents, e.g. for the generation of hyperpolarised gases using optical pumping cells, for storing hyperpolarised contrast agents or for the determination of the polarisation of a hyperpolarised contrast agent
Definitions
- the present disclosure relates to methods for nuclear spin polarization enhancement at very low magnetic fields (e.g., significantly lower than magnetic field of Earth of 50 microTesla) via signal amplification by reversible exchange.
- P 10 ⁇ 6 -10 ⁇ 5
- P 10 ⁇ 6 -10 ⁇ 5
- heteronuclei e.g. 15 N, 13 C
- d-DNP dissolution dynamic nuclear polarization
- parahydrogen abbreviated here as p-H 2 or para-H 2
- PHIP Parahydrogen-Induced Polarization
- SABRE Signal Amplification by Reversible Exchange
- SABRE generally uses an organometallic catalyst to transiently co-locate para-H 2 and the target substrate molecule in a low-symmetry complex in solution.
- low field e.g., 5-7 mT
- net spin order can be transferred from the para-H 2 to the spins of the substrate via scalar couplings.
- achieving efficient hyperpolarization via SABRE has been limited to protons, which depolarize quickly (T 1 of seconds), precluding metabolic tracking on biologically relevant timescales. It also presents background issues from water.
- Heteronuclei such as 15 N are much more attractive for hyperpolarization because they often have long polarization lifetimes or singlet population relaxation times (T S ) in special cases exceeding ten minutes.
- SABRE derived proton hyperpolarization can be transferred to heteronuclei, but the associated efficiency is low, producing only ⁇ 0.03% polarization. Accordingly, there exists a need for methods of hyperpolarization of heteronuclei.
- a method of hyperpolarizing heteronuclei comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; and (b) applying a magnetic field with a strength of less than 50 ⁇ T to the mixture, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus.
- aspects of the present disclosure include methods of performing NMR experiments, methods of obtaining MRI images, and other methods of in vivo imaging.
- FIG. 1A , FIG. 1B , and FIG. 1C is a diagram of the experimental setup for SABRE-SHEATH using a 5 mm NMR tube and the magnetic shield; para-H 2 gas is supplied from a pressurized tank, regulated (via a flow meter), and bubbled through 1/16 in. tubing placed inside the 5 mm NMR tube under 1-7 atm para-H 2 pressure. “Used” para-H 2 gas leaves the NMR sample via an exhaust line.
- FIG. 1B is a diagram of in situ SABRE (9.4 T) and low-field (ex situ) SABRE performed using a 9.4 T NMR magnet and within its fringe field, respectively. All NMR detection was performed at 9.4 T.
- FIG. 1C shows the sequence of events for SABRE-SHEATH hyperpolarization.
- FIG. 2A is a generalized representation of AA′BB′ showing relevant spin-spin couplings.
- FIG. 2B shows a AA′BB′ spin system formed by two Ir-hydride protons and two 15 N sites of two exchangeable 15 N-pyridines shown in the structural diagram of the activated Ir-IMes catalyst using 15 N-Py substrate.
- FIG. 3A illustrates an initial state in the z-direction (population on the diagonal element) rotating about a Hamiltonian along x.
- This Hamiltonian has real positive off-diagonal and zero diagonal elements.
- FIGS. 3B and 3C illustrate the SABRE-SHEATH hyperpolarization process.
- FIG. 3B shows hyperpolarization transfer dictated by eq 5a.
- the off-diagonal elements, ⁇ J AB /2 are real and negative (isomorphic with ⁇ x ); hence, this part of the Hamiltonian is depicted along ⁇ x.
- S A S B on the diagonal is represented by a vector along +z.
- FIG. 3C shows hyperpolarization transfer dictated by eq 5b according to the same principles:
- S 0 T ⁇ population on the diagonal along +z is rotated into a population of
- initial and final states are represented by the most faded and most solid vectors, respectively.
- FIGS. 4A, 4B, 4C, and 4D depict single-shot 15 N-NMR spectra from 15 N-pyridine ( 15 N-Py) SABRE experiments.
- FIG. 4A shows a SABRE-SHEATH experiment with Ir-catalyst/ 15 N-Py concentrations of 0.24 mM and 4 mM respectively. Detected 30,000-fold signal enhancement corresponds to ⁇ 10% polarization.
- FIG. 4B shows that increase of Ir-catalyst/ 15 N-Py concentrations results in the absolute NMR signal amplification, but relative enhancement and polarization levels decrease. An in-phase triplet split by 11 Hz is found, in both, 4 A and 4 B.
- FIG. 4C shows that when attempting 15 N SABRE at the conditions optimized for proton hyperpolarization (6 ⁇ 4 mT) an anti-phase triplet with lower enhancement is observed.
- FIGS. 5A, 5B, 5C AND 5D show 1 H-NMR spectra obtained via SABRE from 14 N-Py vs. 15 N-Py experiments.
- SABRE polarization was conducted in both the ⁇ 6 ⁇ 4 mT field ( FIGS. 5A and 5B ) and in the shield ( FIGS. 5C and 5D ) for 14 N-Py vs. 15 N-Py at 63 mM Py and 6.3 mM catalyst concentrations.
- 1 H-SABRE enhancement levels are shown for the ortho-proton of Py ( ⁇ 8.5 ppm) of each spectrum.
- the hydride region ( ⁇ 22.8 ppm) is shown, highlighting the significant difference in line shape between 15 N-Py and 14 N-Py: a sharp singlet of 14 N-Py vs. anti-phase resonance of 15 N-Py.
- FIG. 6A shows a 1 H thermal NMR spectrum of 2 mM activated Ir-IMes catalyst solution with 48 mM 15 N-pyridine.
- FIG. 6B shows a 1 H NMR spectrum of hyperpolarized 15 N-Py via conventional low-field (6 ⁇ 4 mT) SABRE. The resonances labeled with dashed lines correspond to catalyst-associated Py.
- FIG. 6C-F show 15 N NMR spectra of 15 N-Py hyperpolarized by SABRE-SHEATH.
- FIG. 6C shows an NMR spectrum of 15 N-Py ( ⁇ free ⁇ 300) sample corresponding to completely activated catalyst solution (as validated by 1 H NMR using conventional low-field SABRE through achieving efficient enhancement of Py proton polarization, and also validated through in situ detection of the disappearance of SABRE hyperpolarized Ir-hydride intermediate species).
- FIG. 6C shows an NMR spectrum of 15 N-Py ( ⁇ free ⁇ 300) sample corresponding to completely activated catalyst solution (as validated by 1 H NMR using conventional low-field SABRE through achieving efficient enhancement of Py proton polarization, and also validated through in situ detection of the disappearance of SABRE hyperpolarized Ir-hydride intermediate species).
- FIG. 6D shows an 15 N NMR spectrum of a 15 N-Py sample corresponding to maximum SABRE-SHEATH signal intensity ( ⁇ free ⁇ 3600) achieved with ⁇ 20 min of para-H 2 bubbling (with a ⁇ 20% duty cycle, para-H 2 bubbling at this step was used for sample-degassing purposes; actual para-H 2 bubbling for SABRE-SHEATH was only ⁇ 30 s) after acquisition of the spectrum shown in FIG. 6C (but with the same para-H 2 bubbling time of ⁇ 30 s for SABRE-SHEATH hyperpolarization).
- FIG. 6E shows an 15 N NMR spectrum ( ⁇ free ⁇ 185) of 15 N-Py sample after it was exposed to air; the spectrum is recorded ⁇ 23 min after spectrum shown in FIG.
- FIG. 6F shows an 15 N NMR spectrum of 15 N-Py sample after SABRE-SHEATH intensities ( ⁇ free ⁇ 3600) fully recovered from exposure to air; the spectrum was recorded ⁇ 31 min after the spectrum shown in FIG. 6C .
- FIG. 7A shows a schematic of SABRE showing 15 N-Py and para-H 2 exchange on the activated Ir-IMes catalyst producing efficient 15 N hyperpolarization.
- FIG. 7B is an 15 N NMR spectrum of HP 4 mM 15 N-Py (0.24 mM catalyst) via SABRE-SHEATH procedure using ⁇ 6 atm of para-H 2 pressure.
- FIG. 7C shows the corresponding 15 N reference signal from neat 15 N-Py.
- FIG. 7D is a graph depicting 15 N SABRE-SHEATH signal dependence on the para-H 2 flow rate (sccm) at various para-H 2 pressures: 1.0, 2.7, 5.1, and 7.1 atm. The data acquired in FIG.
- FIGS. 8A, 8B, 8C, 8D, 8E and 8F depict a summary of 15 N relaxation times T 1 at the microtesla ( ⁇ T) field inside the magnetic shield (T 1 ⁇ T ) and at 9.4 T (T 1 9T ) and percentage 15 N polarization (% P) for 15 N SABRE-SHEATH of 15 N-Py for various Ir-IMes catalyst and 15 N-Py concentrations.
- FIGS. 8A and 8E depict a dilution series corresponding to ⁇ 1:16 catalyst to 15 N-Py ratio.
- FIGS. 8B and 8F depict a series of catalyst/ 15 N-Py solutions with fixed catalyst concentration.
- FIGS. 8C and 8D depict a series of catalyst/ 15 N-Py solutions with fixed 15 N-Py concentrations at 100 mM and 20 mM.
- FIGS. 9A, 9B, 9C, 9D, 9E and 9F depict a series of NMR spectra comparing 13 C and 15 N SABRE signal enhancements.
- FIG. 9A depicts 15 N SABRE using SABRE-SHEATH at T field.
- FIG. 9B depicts 15 N SABRE using SABRE-SHEATH at ⁇ 6 mT for a 63 mM 15 N-Py sample with 6 mM of Ir-IMes catalyst.
- FIG. 9C shows a thermally polarized reference spectrum of 12.5 M 15 N-Py used as the polarization enhancement reference for 15 N SABRE.
- the intensity scale for the spectrum corresponding to the conventional (low-field) SABRE at ⁇ 6 mT is zoomed in to twice the level of the T SABRE 15 N spectrum (shown in 9 A), while the 15 N-Py reference spectrum (shown in 9 C) is zoomed in 12-fold.
- FIG. 9D shows 13 C SABRE conducted on the same sample at T field and
- FIG. 9E shows 13 C SABRE at ⁇ 6 mT.
- FIG. 9F shows the 13 C polarization/signal reference in neat methanol (24 M at ⁇ 1.1% natural abundance of 13 C. All of the 13 C SABRE spectra are plotted on the same intensity scale.
- the polarization enhancements ( ⁇ ) for selected peaks are shown for their respective spectra.
- RF pulse width (pw) 128 ⁇ s (90°)
- spectra width (sw) 19 840 Hz
- acquisition time (acq) 0.5 s.
- the image was post-processed with zero filling to 256 ⁇ 256 points for enhanced presentation.
- FIGS. 11A, 11B, 11C, 11D, 11E and 11F illustrate the SABRE of “neat” natural abundance 15 N (0.36%) pyridine (Py).
- FIG. 11A depicts a 15 N SABRE-SHEATH hyperpolarized spectrum and the corresponding thermally polarized reference spectrum after 192 signal averages.
- FIG. 11B depicts a 1 H SABRE spectrum of a hyperpolarized sample in a milliTesla magnetic field ( ⁇ 6 mT) and the corresponding NMR spectrum using a thermally polarized sample.
- FIG. 11A depicts a 15 N SABRE-SHEATH hyperpolarized spectrum and the corresponding thermally polarized reference spectrum after 192 signal averages.
- FIG. 11B depicts a 1 H SABRE spectrum of a hyperpolarized sample in a milliTesla magnetic field ( ⁇ 6 mT) and the corresponding NMR spectrum using a thermally polarized sample.
- FIG. 11C depicts the effect of the para-H 2 flow rate (measured in standard cubic centimeters per minute or sccm) on 15 N signal enhancement at ⁇ 90 mM catalyst concentration under five para-H 2 pressure values.
- FIG. 11D depicts the effect of [Py] to [catalyst] ratio on 15 N signal enhancement using 120 sccm flow rate under ⁇ 7 atm of para-H 2 pressure.
- FIG. 11E depicts the 15 N SABRE-SHEATH dependence (modeled as exponential decay) as a function of the sample exposure to the microTesla magnetic field after stopping para-H 2 bubbling time.
- FIG. 11F depicts the 15 N T 1 decay at 9.4 T.
- the experiments in panels E and F are conducted using ⁇ 90 mM catalyst concentration ( ⁇ 140:1 [Py] to [catalyst] ratio) at 120 sccm flow rate and ⁇ 7 atm para-H 2 pressure.
- FIGS. 12A and 12B illustrate diagrams of para-H 2 exchange and 15 N SABRE-SHEATH hyperpolarization in the absence ( FIG. 12A ) and in the presence ( FIG. 12B ) of 14 N-Py excess.
- the exchange with 14 N-Py does not cause a significant reduction in the spin order of the para-H 2 pool.
- Both equatorial pyridines of the active complex undergo the chemical exchange with free Py in solution, while the axial pyridine (labeled as “Py”) is not exchangeable.
- FIGS. 13A and 13B illustrate spin systems used for analytical derivation of the resonance conditions for ( FIG. 13A ) 15 N-Py solutions and ( FIG. 13B ) n.a. Py solutions.
- J HN J H′N′
- J HN′ J H′N .
- Couplings to spins in axial positions are ignored because they generally are smaller than equatorial couplings and play a subordinate role. (Additionally, this site does not exchange with free substrate.)
- FIG. 14 shows the chemical structures and maximum 15 N SABRE-SHEATH signal enhancements obtained for pyridine, picolines, and lutidines in neat liquids using ⁇ 45 mM catalyst concentration and naturally abundant levels of 15 N ( ⁇ 0.35%) under ⁇ 7 atm of para-H 2 pressure and flow rate of 100-120 sccm.
- the value labeled with a single asterisk (*) corresponds to the optimized catalyst concentration of ⁇ 90 mM
- the values labeled with double asterisks (**) correspond to the experiments conducted at 5 atm of para-H 2 and the flow rate of 60 sccm
- n.d. stands for none detected.
- FIG. 15 demonstrates the SABRE-SHEATH hyperpolarization of imidazole and the change in 15 N chemical shift with protonation of the imidazole nitrogen.
- FIG. 16A is a chemical structure depicting the most probable Ir-catalyst complex and the exchange of para-H 2 and Py substrate when catalyst is activated with n.a. Py in a SABRE-SHEATH experiment.
- FIG. 16C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- FIG. 16B shows 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 17A is a chemical structure depicting the most probable Ir-catalyst complex (from the perspective relevant to 15 N SABRE-SHEATH hyperpolarization process) and the exchange of para-H 2 and Py-d substrate.
- the catalyst is activated with natural Py-d 5 (99.5% deuterium enrichment) and natural abundance level of 15 N.
- FIG. 17B shows 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 17C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- FIG. 18A is a chemical structure depicting the most probable Ir-catalyst complex (from the perspective relevant to 15 N SABRE-SHEATH hyperpolarization process) and the exchange of para-H 2 and 15 N enriched (99% 15 N) 15 N-Py substrate.
- the catalyst is activated with 15 N-Py.
- FIG. 18B shows the 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 18C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- FIG. 19A is a chemical structure depicting the most probable Ir-catalyst complex (from the perspective relevant to 15 N SABRE-SHEATH hyperpolarization process) and the exchange of para-H 2 and 15 N-Py/Py-d 5 substrates.
- the catalyst is activated with 15 N-Py, which is reflected in the occupant of nonexchangeable (axial) ligand position.
- FIG. 19B shows the 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 19C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- FIG. 20A is a chemical structure depicting the most probable Ir-catalyst complex (from the perspective relevant to 15 N SABRE-SHEATH hyperpolarization process) and the exchange of para-H 2 and 15 N-Py/Py-d 5 substrates.
- FIG. 20B shows the 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 20C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- FIG. 21A is a chemical structure depicting the most probable Ir-catalyst complex (from the perspective relevant to 15 N SABRE-SHEATH hyperpolarization process) and the exchange of para-H 2 and 15 N-Py/n.a. Py substrates.
- FIG. 21B shows the 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 21C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- FIG. 22A is a chemical structure depicting the most probable Ir-catalyst complex (from the perspective relevant to 15 N SABRE-SHEATH hyperpolarization process) and the exchange of para-H 2 and 15 N-Py/n.a. Py substrates.
- the catalyst is activated with n.a. Py, which is reflected in the occupant of nonexchangeable (axial) ligand position.
- FIG. 22B shows the 15 N T 1 decay of hyperpolarized signal measured at 9.4 T using small degree ( ⁇ 7°) excitation RF pulse.
- FIG. 22C shows the decay and fitting model of 15 N signal detected at 9.4 T as a function of sample exposure time to microTesla magnetic field of the shield after stopping para-H 2 flow.
- SABRE-SHEATH SABRE in SHield Enables Alignment Transfer to Heteronuclei.
- the methods include using transition metal catalysts for nuclear spin polarization enhancement in neat liquids via SABRE-SHEATH.
- the methods offer significant advantages over existing methods of hyperpolarization of heteronuclei, including the ability to perform the experiments on a shorter timescale with greater polarization and signal enhancement.
- the disclosed methods demonstrate up to 10% polarization directly on 15 N, corresponding to signal gains of 30,000 fold at 9.4 T.
- the conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term.
- the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present.
- the phrases “at least one of A, B, . . . and N” or “at least one of A, B, . . . N, or combinations thereof” are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.
- the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
- the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints.
- the expression “from about 2 to about 4” also discloses the range “from 2 to 4.”
- the term “about” may refer to plus or minus 10% of the indicated number.
- “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1.
- Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.
- heterogeneous catalyst means a catalyst that is in a separate phase from the reactants.
- the heterogeneous catalyst used in the methods described herein may be a heterogeneous catalyst in U.S. patent application Ser. No. 14/801,541, the contents of which are incorporated herein in their entirety.
- the heterogeneous transition metal catalyst described herein may also be in U.S. patent application Ser. No. 14/801,541.
- homogeneous catalyst means a catalyst that is in the same phase as the reactants.
- the homogeneous catalyst used in the methods described herein may be a homogeneous catalyst in U.S. patent application Ser. No. 14/801,554, the contents of which are incorporated herein in their entirety.
- the homogeneous transition metal catalyst described herein may also be in U.S. patent application Ser. No. 14/801,554.
- isotopically enriched means that in a composition comprising a plurality of molecules of the compound, the amount (e.g., fraction, ration or percentage) of the plurality of molecules having the particular isotope at the particular atom is substantially greater than the natural abundance of the particular isotope, due to synthetic enrichment of the particular atom with the particular isotope.
- a composition comprising a compound with an isotopically enriched 15 N atom at a particular location includes a plurality of molecules of the compound where, as a result of synthetic enrichment, the percentage of the plurality of molecules having 15 N at that location is greater than about 1% (the natural abundance of 15 N is substantially less than 1%), and in many cases is substantially greater than about 1%.
- a composition comprising a compound with an isotopically enriched atom at a particular location may include a plurality of molecules of the compound, where the amount of the plurality of molecules having the isotope at the location may be at least about two-or-more-fold greater than the natural abundance of the isotope, including but not limited to at least about two-fold, at least about three-fold, at least about four-fold, at least about five-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 60-fold, at least about 70-fold, at least about 80-fold, at least about 90-fold, at least about 100-fold, and at least about 200-fold, among others.
- a composition comprising a compound with an isotopically enriched atom at a particular location also may include a plurality of molecules of the compound where, as a result of synthetic enrichment, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%, of the plurality of molecules have the isotope at the location.
- natural abundance refers to the abundance of the isotope as naturally found on the planet Earth.
- the natural abundance of 15 N on the planet Earth is generally regarded to be about 0.37% (i.e., substantially less than about 1%), while the natural abundance of deuterium (D) on the planet Earth is generally regarded to be about 0.015% (i.e., substantially less than about 1%).
- described herein is a method of directly transferring para-H 2 polarization to heteronuclei, using extremely low magnetic fields (microTesla), without the need of rf irradiation or pulses.
- the heteronuclei may comprise 15 N, 13 C, 29 Si, 31 P or 19 F.
- frequency differences between the para-H 2 -derived hydride protons and the to-be-polarized target nuclei should preferably match the J-coupling interactions that connect the polarization source and target nuclei.
- nascent parahydrogen protons of Ir-hydride to heteronuclei e.g., 15 N-Py
- efficient transfer of hyperpolarization from nascent parahydrogen protons of Ir-hydride to heteronuclei e.g., 15 N-Py
- the frequency difference between the Ir-hydride protons and 15 N on the complex matches specific J-coupling terms, as displayed in FIG. 2 .
- (1) ⁇ v HN
- (2) where ⁇ v HN v H ⁇ v N is the frequency difference between Ir-hydride protons and catalyst-bound 15 N, and the J-couplings are as depicted in FIG. 2 .
- AA′BB′ spin system The two hydride protons and two 15 N nuclei within the two exchangeable substrates form an AA′BB′ spin system. Within this AA′BB′ system, the polarization transfer takes place.
- hyperpolarization transfer process in AA′BB′ systems may be understood by choosing the right basis set and using the following equations with the singlet-triplet basis applied to both the A spin pair and the B spin pair:
- H AA ′ ⁇ BB ′ ⁇ S 0 A ⁇ S 0 B ⁇ ⁇ T - A ⁇ T + B ⁇ ⁇ S 0 A ⁇ S 0 B ⁇ ⁇ T - A ⁇ T + B ⁇ ( - ( J AA + J BB ) - ⁇ ⁇ ⁇ J AB / 2 - ⁇ ⁇ ⁇ J AB / 2 ⁇ J AB 2 - ( v A - v B ) ) ( 5 ⁇ a )
- H AA ′ ⁇ BB ′ ⁇ S 0 A ⁇ S 0 B ⁇ ⁇ T - A ⁇ T + B ⁇ ⁇ S 0 A ⁇ S 0 B ⁇ ⁇ T - A ⁇ T + B ⁇ ( - ( J AA + J BB ) - ⁇ ⁇ ⁇ J AB / 2 - ⁇ ⁇ ⁇ J AB / 2 - ( v A - v B
- the form of eq 5a implies that population can be transferred from
- the off-diagonal elements can take full effect and rotate population from
- the off diagonal elements ⁇ J AB /2 are real and negative (isomorphic with ⁇ x ); hence, they are depicted as a vector along ⁇ x.
- This process forms hyperpolarization in the T + state of the targeted (B) spins corresponding to detectable magnetization.
- the first resonance condition given in eq 1 can be deduced (by equalizing the diagonal elements).
- eq 5b shows that hyperpolarization can be transferred from the
- T ⁇ S 0 when the diagonal elements in the Hamiltonian are equalized ⁇ v B ⁇ J AA ⁇ v A ⁇ J BB , as illustrated in FIG. 3C , establishing the second resonance condition given in eq 2.
- Hyperpolarization can be observed because T B is depleted, in effect creating overpopulation in T + , just as predicted by the first resonance condition as well.
- Over-population in T B + corresponds to alignment with the main magnetic field only for species with positive ⁇ (e.g., 13 C); for species with negative ⁇ (such as 15 N), overpopulation in T + corresponds to anti-alignment with the main magnetic field—in accordance with the experimental observations detailed below.
- J HH ⁇ 9 Hz
- all resonance conditions (those of eqs 1 and 2) are satisfied simultaneously, and a useful hyperpolarization transfer field can be estimated as B 0-transfer ⁇ J HH /( ⁇ A ⁇ B ) ⁇ 0.26 ⁇ T, assuming a J-coupling term (J HH ) of ⁇ 9 Hz ( FIG. 2 ).
- the resonance conditions need not be met precisely, because continuous exchange of para-H 2 and substrate reduce the residence times typically to about 0.2 s.
- the mismatch has only a modest effect on the population transfer. This implies that the effect of multiple exchanges will tend to equilibrate the populations of the states
- This assertion is also backed by the experimental observation that the specified resonance matching conditions do not have to be met exactly; instead, if the magnetic field has the adequate order of magnitude, then the desired effect is observed. In this sense, the magnetic field simply has to be low enough, however “true” zero field would likely not produce the observed effects because a sufficient difference between T + and T ⁇ states must prevail in order to create alignment along the residual magnetic field.
- the magnetic field causes the matching of the resonance frequency of parahydrogen with the resonance frequency of at least one hyperpolarizable heteronucleus in a compound.
- the resonance frequencies of parahydrogen and the hyperpolarizable heteronuclei are different.
- the resonance frequencies of parahydrogen and the hyperpolarizable heteronuclei are within an order of magnitude of each other.
- the magnetic field is less than the Earth's magnetic field. In certain embodiments, the magnetic field is less than 50 ⁇ T, less than 45 ⁇ T, less than 40 ⁇ T, less than 35 ⁇ T, less than 30 ⁇ T, less than 25 ⁇ T, less than 20 ⁇ T, less than 15 ⁇ T, less than 10 ⁇ T, less than 5 ⁇ T, less than 4 ⁇ T, less than 3 ⁇ T, less than 2 ⁇ T, or less than 1 ⁇ T.
- the magnetic field is about 0.1 to about 50 ⁇ T, about 0.1 to about 45 ⁇ T, about 0.1 to about 40 ⁇ T, about 0.1 to about 35 ⁇ T, about 0.1 to about 30 ⁇ T, about 0.1 to about 25 ⁇ T, about 0.1 to about 20 ⁇ T, about 0.1 to about 15 ⁇ T, about 0.1 to about 10 ⁇ T, about 0.1 to about 5 ⁇ T, about 0.1 to about 4 ⁇ T, about 0.1 to about 3 ⁇ T, about 0.1 to about 2 ⁇ T, about 0.1 to about 1 ⁇ T, about 0.1 to about 0.5 ⁇ T, about 0.1 to about 0.4 ⁇ T, about 0.1 to about 0.3 ⁇ T, about 0.2 to about 0.4 ⁇ T, or about 0.2 to about 0.3 ⁇ T.
- the disclosed method may include bubbling para-H 2 through a solution containing activated catalyst and 15 N-Py inside a gi-metal magnetic shield where the hyperpolarization is created ( FIG. 1 ). Subsequently, the sample may be transferred into an NMR magnet for detection by a simple 90° pulse resulting in in-phase signal. This in-phase signal may be useful in imaging applications, where the associated broader lines would suffer signal cancellations if the signals were anti-phase.
- SABRE-SHEATH polarization can be demonstrated by placing the NMR tube in a 305 mm-long magnetic shield (Lake Shore Cryotronics, P/N 4065) with ⁇ 30 s of bubbling of para-H 2 . After this ⁇ 30 s polarization period, para-H 2 delivery can be stopped, and the NMR tube quickly transferred ( ⁇ 4 s) to a 9.4 T Bruker Avance III NMR spectrometer to detect the SABRE-SHEATH polarization through conventional 1D-NMR. Both 15 N and 1 H pulse-acquire NMR experiments can be conducted.
- FIG. 4 shows results of SABRE-SHEATH experiments. At concentrations of 4 mM 15 N-Py (and 0.24 mM catalyst), a 30,000-fold polarization enhancement over the thermal level is achieved ( FIG. 4A ).
- the thermal 15 N polarization at 9.4 T and room temperature is ⁇ 3.3 ⁇ 10 6 , thus this enhancement corresponds to a 15 N polarization of ⁇ 10%.
- This polarization is not adjusted for relaxation that may occur during sample transfer from magnetic shield to detection region, and the polarization created in the shield may be larger.
- FIG. 4B Spectra obtained with the 63 mM 15 N-pyridine (6.3 mM catalyst, FIG. 4B ) illustrates that with increasing concentrations, the absolute signal can be further increased but the corresponding enhancement level (and the respective polarization, P) is diminished to 3,000 fold (P ⁇ 1%).
- the reduced enhancements observed with increasing concentrations may be limited by three factors: (i) the finite amount of dissolved para-H 2 may limit the available hyperpolarization that can be passed to 15 N-Py molecules; (ii) the Ir-catalyst and Py concentrations modulate Py residency time, which may affect the efficiency of SABRE polarization transfer; (iii) NHC Ir-catalyst may be a source of T 1 relaxation, which in turn may limit the maximum polarization level.
- the spectral pattern observed for the free Py in the SABRE-SHEATH experiments ( FIGS. 4A and 4B ) is as clean in-phase triplet because the dominant two-bond J-coupling between 15 N and the ortho-Py-protons 2 J NH is ⁇ 11 Hz.
- the 15 N-triplet is associated with lower enhancements, but also, it is purely anti-phase, which makes this signal much less useful in imaging applications, because of partial signal cancellation that occurs when spectral lines are broadened.
- FIG. 5 contrasts 1 H hyperpolarization levels observed on 15 N-Py versus those on 14 N-Py.
- 1 H-SABRE on 15 N-Py is less effective than that on 14 N-Py regardless of whether the experiments are directed to 1 H hyperpolarization (SABRE at ⁇ 6 ⁇ 4 mT, FIGS. 5A and 5B ) or hyperpolarization transfer to 15 N (SABRE in the magnetic shield, FIGS. 5C and 5D ).
- polarization transfer strategies e.g., 1 H ⁇ 15 N via INEPT
- FIG. 6A and FIG. 6B demonstrate the conventional low-field (achieved via para-H 2 exchange at 6 ⁇ 4 mT) SABRE proton NMR spectroscopy and corresponding NMR spectrum of the thermal reference. 1 H hyperpolarization levels are generally suppressed when using 15 N-Py vs natural abundance Py. Nevertheless, signal enhancements of ⁇ 140 for ortho-protons of 15 N-Py were observed under these conditions.
- FIG. 6D shows a 15 N NMR spectrum taken from a SABRE-SHEATH HP sample, with 15 N P ⁇ 3600. Yet subsequent (re)exposure of this sample to air (via air bubbling for ⁇ 5 s) resulted in significant reduction of SABRE-SHEATH efficiency to ⁇ 185 ( FIG. 6E ).
- the maximum achieved 15 N P of 15 N-Py described herein was ⁇ 10%, corresponding to F z 30,000 at the time of signal detection in the 400 MHz NMR spectrometer ( FIG. 7A-C ).
- the actual initial 15 N polarization created within the shield prior to sample transfer is likely even higher, because of T 1 relaxation losses suffered in transit (requiring ⁇ 5 s).
- the respective effects of para-H 2 pressure and flow rate could not be reliably discriminated using the flow meter because its throughput (in mL ⁇ atm ⁇ s ⁇ 1 ) is proportional to the product of volume and pressure per unit time.
- the same setting of the flow meter at two different pressures would result in two different mass flow rates measured in standard cubic centimeters per minutes (sccm). Therefore, a digital mass-flow controller regulating flow irrespective of bubbling pressure was utilized instead for these measurements, where the flow rate was varied at different pressures resulting in isobar curves ( FIG. 7D ).
- the isobars at 1.0 and 2.7 atm produced lower signal at higher flow rates when compared to those at 5.1 and 7.1 atm.
- higher pressure is still more desirable to maximize 15 N signal (and 15 N P), but from the perspective of more efficient gas mixing and para-H 2 delivery (moles per unit of time) to the catalyst (in this setup using para-H 2 bubbling in the NMR tube). Therefore, such bubbling SABRE-SHEATH hyperpolarization setups may benefit from operation at significantly higher para-H 2 pressures to maximize the amount of para-H 2 available for SABRE processes.
- the reaction temperature may modulate the residence time of both the Py substrate and para-H 2 , thereby altering exchange rates.
- previous studies of conventional low-field SABRE have observed temperature dependences of SABRE hyperpolarization levels.
- FIG. 7E demonstrates an explicit temperature dependence of 15 N SABRE-SHEATH polarization, with greater signal enhancements measured at lower temperatures. While others have identified that for 1 H SABRE the performance for this catalyst peaks at >40° C.
- the discrepancy may be explained by several factors, including that (i) higher para-H 2 pressures (and consequently solution concentrations) were used and (ii) the interactions (the relevant spin-spin couplings) leading to NMR hyperpolarization in homonuclear (for proton SABRE hyperpolarization) and heteronuclear (for SABRE-SHEATH 15 N hyperpolarization) are different, possibly giving rise to differing useful residency times for SABRE hyperpolarization.
- T 1 measurements were performed by inducing 15 N SABRE-SHEATH hyperpolarization in the magnetic shield, which was followed by a variable delay for polarization decay in the magnetic shield (microtesla), in the fringe field of the main magnet ( ⁇ 6 mT), or in the 9.4 T field of the magnet.
- Representative corresponding data sets showing the dependence of the NMR signal on the delay time at these fields are provided in FIG. 7F , exhibiting the overall trend: 15 N T 1 9.4T > 15 N T 1 6 mT > 15 N T 1 ⁇ T .
- T 1 may modulate the build-up rate and the maximum attainable polarization, as can be seen in a dilution series (6 mM/100 mM, 1.2 mM/20 mM, and 0.24 mM/4 mM for the fixed [catalyst]/[ 15 N-Py] ratio) shown in FIG. 8A , where ⁇ T T 1 gains are correlated with gains in P max (defined as 15 N P after SABRE-SHEATH polarization accumulation for a period of time greater than 3T 1 , FIG. 8E ).
- FIG. 8A provides additional evidence showing the trends for P max and T 1 for solutions with fixed [catalyst] and variable ([ 15 N-Py]([catalyst]/[ 15 N-Py] ratio was varied). While the ⁇ T T 1 remained at approximately the same level of ⁇ 10 s, the increase in [ 15 N-Py] resulted in the corresponding decrease of P max ( FIG. 8F ).
- Hyperpolarization of aromatic 13 C sites of 15 N-Py via SABRE in general may be useful due to (i) greater 13 C natural abundance vs 15 N, (ii) more readily available detection hardware, and (iii) better detection sensitivity.
- SABRE-SHEATH relies on the J-coupling between exchangeable protons of Ir-hydride and the target nucleus, its efficiency may be reduced because the requisite long-range (three-, four-, and five-bond) J-couplings are weak.
- An adequate field-cycling scheme for increasing 13 C hyperpolarization levels may be determined that is suitable for utilizing 13 C SABRE-SHEATH.
- double-resonance experiments (for polarization transfer from 1 H or 15 N to 13 C) may also more efficiently hyperpolarize 13 C spins via SABRE.
- the demonstrated % P of 15 N by the SABRE-SHEATH method is equal to or greater than 15 N hyperpolarization achieved by d-DNP and PHIP methods, yet requires only seconds (vs tens of minutes to hours) of hyperpolarization time.
- the easy access to 15 N hyperpolarization by SABRE-SHEATH prompted a feasibility study of HP 15 N MRI.
- a slice-selective 2D 15 N MR imaging experiment was performed using a preclinical 4.7 T MRI scanner ( FIG. 10B ).
- a modified setup was used to hyperpolarize ⁇ 1.2 mL of solution containing 20 mM 15 N-Py, corresponding to ⁇ 24 ⁇ mol of 15 N Py hyperpolarized to P of ⁇ 1% at the time of the detection after a ⁇ 30 s long transfer from the magnetic shield to the bore of the 38 mm i.d. 15 N volume coil of a triple-resonance ( 1 H/ 15 N/ 31 P) RF probe ( FIG. 10A ).
- the modified setup utilized a high-pressure HPLC column (Western Analytical Products, Lake Elsinore, Calif., USA, item no.
- an axial 2D 15 N MR image with 2 ⁇ 2 mm 2 spatial resolution was successfully acquired showing HP liquid placed inside a 6.6 mm i.d. high-pressure HPLC column. Furthermore, this image was acquired in ⁇ 0.4 s, demonstrating the feasibility of subsecond 15 N MRI of HP contrast agents.
- the detection sensitivity of 15 N HP compounds can be further enhanced by implementation of MRI pulse sequences yielding more SNR (e.g., balanced steady-state free precession (bSSFP)).
- bSSFP balanced steady-state free precession
- the long-lived 15 N hyperpolarization can potentially also be transferred to protons for more efficient indirect detection. This practice could boost sensitivity by approximately 10-fold because the detection sensitivity is directly proportional to the gyromagnetic ratio ⁇ and ⁇ ( 1 H) ⁇ 10 ⁇ ( 15 N).
- N-heterocycles which are already amenable to SABRE hyperpolarization, represent the fundamental molecular frameworks for many classes of biologically relevant compounds: DNA and RNA bases, vitamins, and numerous drugs and drug building blocks. Therefore, a number of potential HP contrast agents can be employed where N sites amenable to 15 N SABRE-SHEATH can serve as hyperpolarization storage sites for imaging in vivo processes. For example, nicotinamide is linked to many diseases including Alzheimer's disease, cancer, and anxiety, and therefore may be a useful HP probe for these diseases. Py-based HP 15 N agents have been shown useful for pH sensing using the d-DNP hyperpolarization method.
- 15 N-SABRE-SHEATH produces 15 N-Py and 15 N-nicotinamide with ⁇ 6 times greater hyperpolarization levels compared to those achieved by d-DNP with a much more rapid hyperpolarization process ( ⁇ 1 min vs ⁇ 2 h), highlighting the advantages of 15 N SABRE-SHEATH for this class of compounds.
- nitrogen-containing compounds such as pyridine, nicotinamide and others can be enriched with 15 N using simple chemistry that either allows direct heteroatom replacement with 15 N isotope or through a ring opening and closure, frequently using 15 NH 4 Cl as a very cheap source of spin label.
- the labor-intensive de novo synthesis of complex 15 N biomolecules can be largely obviated. Therefore, the 15 N isotopic enrichment required for 15 N SABRE-SHEATH may produce inexpensive contrast agents. Combined with the very simple setup and instrumentation required for SABRE-SHEATH, it may enable fast, high-throughout, scalable, and low-cost production of HP 15 N contrast agents.
- SABRE-SHEATH techniques can also achieve hyperpolarization of neat liquids—each comprised only of an otherwise pure target compound and millimolar concentrations of dissolved catalyst, without any additional diluting solvent.
- such liquids could be used directly as hyperpolarized MRI contrast agents; the use of organic solvents is obviated, and a greater payload for the concentrated agents is observed.
- the 15 N signal enhancement was approximately independent of the para-H 2 pressure (and solution concentration according to Henry's law), indicating that the flux of the available para-H 2 spin bath (the source of spin order) was indeed the limiting factor; that is, the potential possibility of exchanging more para-H 2 per unit time would likely yield greater 15 N signal enhancements. Larger para-H 2 exposure can be attained by higher pressures and smaller bubbles/better gas-phase-liquid-phase mixing.
- the 15 N spin-lattice relaxation time is significantly shorter in microTesla fields than at high field (9.4 T), 5.5 ⁇ 0.5 versus 60.8 ⁇ 0.6 s, respectively ( FIG. 11E and FIG. 11F ), and such efficient relaxation results in SABRE-SHEATH 15 N enhancements reaching significantly lower steady-state levels after the hyperpolarization procedure.
- the supply of para-H 2 is limited because only ⁇ 0.1 mmol/s pass through the tube at the maximum flow rate of 150 sccm, whereas 90 mM catalyst (in ⁇ 0.4 mL volume) alone is capable of exchanging of ⁇ 0.2 to 0.4 mmol/s of H 2 because the hydrogen exchange rate is ⁇ 5-10 per second.
- Ir-hydride protons do not have 100% exchange efficiency with para-H 2 gas. Instead, this exchange is further constricted by at least two bottlenecks: (i) exchange of H 2 between gas and liquid phases and (ii) exchange of dissolved para-H 2 with Ir-hydride.
- Equilibrium H 2 concentration in organic solvents is ⁇ 4 mM/atm; that is, even at the maximum para-H 2 pressure used ( ⁇ 7 atm), para-H 2 concentration is ⁇ 30 mM, at least three times lower than that of the Ir-hydride catalyst at 90 mM concentration.
- the spin order residing in the entire pool of para-H 2 can be selectively channeled to hyperpolarize 15 N nuclei of the exchangeable substrate (e.g., n.a. Py) rather than being depleted by rapidly relaxing 14 N sites acting as hyperpolarization sinks.
- 15 N nuclei of the exchangeable substrate e.g., n.a. Py
- This allows achieving relatively high levels of 15 N hyperpolarization e.g., P 15 N ⁇ 1%
- the 14 N species likely do not deplete the para-H 2 state because the quadrupolar relaxation rate of the 14 N spins is faster than the J-coupling interactions that would otherwise transfer hyperpolarization to the target spins; hence, the 14 N spins are effectively (self)decoupled from the bound para-H 2 .
- the N—H J couplings drive the hyperpolarization transfer; specifically, the term (J HN ⁇ J HN′ )/2 determines the rate of hyperpolarization transfer.
- the 14 N spin can be ignored because the strong quadrupolar interaction decouples the 14 N spin from the depicted spin systems.
- 14 N and other quadrupolar nuclei may act as direct or indirect hyperpolarization sinks (e.g., polarization transfer from Ir-hydride protons to 14 N, D, etc. or from 15 N (after hyperpolarization transfer from para-H 2 ) to 14 N, D, etc.) at low magnetic fields (analogous to interaction between 129 Xe and 131 Xe in xenon lattices), and because the local molecular environment can significantly alter the 15 N effective T 1 in the microTesla field regime, 15 N SABRE-SHEATH of deuterated Py (Py-d 5 ) was studied as well as various mixtures of 15 N-Py and Py-d 5 with 15 N-Py and n.a.
- the Py type (n.a. Py, Py-d 5 , or 15 N-Py) used during the activation period determined the spin configuration of Py in the axial nonexchangeable position of the hexacoordinate Ir-hydride complex, whereas the abundance of the Py type in the mixture determines the most probable type of exchangeable Py in the two equatorial positions.
- Deuteration of to be-polarized 15 N-substrate had the most detrimental effect on microTesla 15 N effective T 1 , a decrease from 5.5 ⁇ 0.5 to 2.2 ⁇ 0.1 s for n.a. Py versus Py-d 5 (row 1 vs row 2 of Table 1).
- microTesla 15 N effective T 1 is greater when the catalyst was first activated with Py-d 5 versus that when catalyst is first activated with 15 N-Py (15.1 ⁇ 2.3 versus 10.1 ⁇ 0.8 s), but the 15 N signal enhancements were somewhat lower ( ⁇ ( ⁇ )400 vs ( ⁇ )520), indicating that at least some polarization losses occurred on the hyperpolarized Ir-hydride due to the presence of deuterium in the catalyst structure.
- the 15 N SABRE-SHEATH of neat liquids is an advantageous tool for efficient hyperpolarization of 15 N spins, particularly at their low natural abundance level.
- One potential use is for rapid compound screening, demonstrated on a series of picolines and lutidines shown in FIG. 14 . It was determined that the presence of a methyl group in position 2 or 6 results in no detectable 15 N hyperpolarization via SABRE-SHEATH, whereas the substituents in other positions result in 15 N signal enhancements levels similar to those of Py. Steric hindrance induced by the presence of methyl groups in ortho positions significantly alters the time scale of the SABRE exchange process or reduces the association constant.
- Picolines and lutidines were chosen because pH-mediated protonation of N-heterocylic compounds can be useful for in vivo pH imaging using conventional proton-based non-hyperpolarized sensing, where the difference in 15 N chemical shift induced by the agent protonation can be useful for pH imaging provided that the agent's pKa is in the physiologically relevant range.
- 15 N centers of the Py class screened here were identified as promising hyperpolarized pH sensors with potential biomedical application to noninvasively image local variances in tissue pH.
- pH imaging using hyperpolarized 15 N heterocycles relies on the modulation of 15 N chemical shift, which changes by up to 100 ppm between protonated and deprotonated states.
- This feature offers a significant sensitivity advantage because only one species requires detection (ratiometric measurements are not needed), and low signal-to-noise ratio would not affect the accuracy of the measurement because the chemical shift reports on the pH.
- hyperpolarized 15 N sites have significantly longer T 1 in aqueous media (>30 s) compared with 13 C bicarbonate ( ⁇ 10 s), which can also be a significant advantage for in vivo applications (especially relevant for applications involving cancer, given the known hallmarks of elevated glycolysis and mildly acidic microenvironments).
- the 15 N signal enhancements reported in FIG. 14 may be increased through improved apparatus design, allowing for better access to the hyperpolarization source of para-H 2 (as well as reduced transit times to high field for detection).
- the combination of heterogeneous SABRE catalysts with the method presented here may allow preparation of pure hyperpolarized liquids because such solid phase catalysts can be separated and recycled.
- the reported 15 N signal enhancement values are already comparable to 15 N enhancements previously reported using dissolution DNP technology and a commercial DNP hyperpolarizer.
- the method reported here achieves the steady-state maximum hyperpolarization level in ⁇ 1 min without sophisticated equipment, versus ⁇ 2 h using expensive DNP hyperpolarizers.
- SABRE for hyperpolarization of 15 N pH sensors can directly lead to useful in vivo applications because the 15 N SABRE-SHEATH procedure is a relatively simple process and because in vivo pH sensors are useful in metabolic biomedical applications.
- Imidazole-based pH sensors have been known in the context of proton Magnetic Resonance Spectroscopy (MRS).
- MRS proton Magnetic Resonance Spectroscopy
- the 15 N chemical shift of imidazole changes by more than 30 ppm upon protonation ( FIG. 15 ).
- pKa of imidazole is ⁇ 7.0 and because it is a relatively non-toxic molecule, it may be a potent pH sensor as a 15 N hyperpolarized contrast agent. It is amenable to SABRE-SHEATH hyperpolarization, as can be seen in FIG. 15 with 15 N signal enhancement of >1,000 with already achievable hyperpolarization level of ⁇ 1% in the initial proof-of-principle demonstration ( FIG. 15 ).
- the SABRE samples were prepared by the addition of an aliquot of 15 N enriched (Sigma-Aldrich, P/N 486183) or natural-abundance Py to a solution of catalyst precursor, resulting in desired concentrations of Py and catalyst.
- the SABRE catalyst was created using the precursor [IrCl(COD)(IMes)].
- the catalyst precursor activation was monitored via in situ detection of HP intermediate Ir-hydride species within a 9.4 T NMR spectrometer by proton NMR spectroscopy using the SABRE effect.
- SABRE experiments in the magnetic shield (microtesla) or in the low magnetic field (fringe field of the 9.4 T magnet) of 6 ⁇ 4 mT ( FIG. 1 ) were performed.
- a freshly prepared sample containing the Ir precursor catalyst and Py in CD 3 OD was placed inside a 5 mm medium-wall NMR tube (3.43 mm i.d.) for SABRE hyperpolarization.
- Normal H 2 gas or para-H 2 gas was bubbled through the methanol-d 4 solution via 1/16 in. o.d. ( 1/32 in. i.d.) tubing inside the NMR tube as shown in FIG. 1 .
- a flow-meter was used to regulate the gas flow at the rate of ⁇ 1 mL ⁇ atm ⁇ s ⁇ 1 .
- the bubbling time and para-H 2 pressure varied from ⁇ 1 to 60 s and from 1 to ⁇ 7 atm, respectively, for SABRE experiments.
- H 2 bubbling used longer time periods and 1 atm pressure as described earlier.
- in situ SABRE experiments at 9.4 T para-H 2 bubbling occurred inside the NMR magnet, and the signal was acquired (3 ⁇ 2 s) after the bubbling was stopped.
- low-field SABRE experiments and SABRE-SHEATH experiments para-H 2 bubbling occurred outside of the NMR detector (in the 6 ⁇ 4 mT fringe field of the NMR magnet) or inside the magnetic shield, respectively ( FIG. 1 ).
- the sample was manually shuttled to the NMR magnet (9.4 T) into the detection coil, and the signal was recorded with typical transit times of 5 ⁇ 2 s.
- the experimental setup was modified in studies of 15 N SABRE-SHEATH signal dependence on the flow rate at four different pressure values by replacing the flow meter ( FIG. 1A ) with a mass flow controller (Sierra Instruments, Monterey, Calif., model no. C100L-DD-OV1-SV1-PV2-V1-S0-C0).
- the NMR signal reference samples for 13 C and 15 N were loaded in standard 5 mm (4.14 mm i.d.) NMR tubes. All NMR experiments were conducted with a single-scan acquisition (90° excitation RF pulse) using 400 MHz Bruker Avance III spectrometer unless noted otherwise.
- the equilibrium signal intensities for 15 N and 13 C samples were too low, and signal averaging was impractical due to excessively long ( ⁇ 1 min) T 1 values. Therefore, external signal reference samples of 12.5 M 15 N-Py and neat methanol (24 M with ⁇ 1.1% natural abundance of 13 C isotope) were employed instead.
- the A REF /A HP ratio was ⁇ 1.85, computed as 4.142/(3.432 ⁇ 1.62), where 4.14 mm is the inner diameter of the standard 5 mm NMR tubes used for NMR signal referencing samples, 3.43 mm is the inner diameter of the medium-pressure tubes used for SABRE samples, and 1.6 mm is the outer diameter of the 1/16 in.
- PTFE tubing inserted into the medium-wall NMR tube for para-H 2 bubbling note that (3.432 ⁇ 1.62) mm 2 corresponds to the effective solution cross-section in the medium-wall NMR tubes used for SABRE experiments, in contrast to 4.142 mm 2 used for signal reference samples).
- P was calculated as the following product: ⁇ P THER , where P THER is the thermal equilibrium nuclear spin polarization of 1 H, 13 C, or 15 N nuclei at 9.4 T and 300 K (3.2 ⁇ 10 ⁇ 5 , 8.1 ⁇ 10 ⁇ 6 , and 3.3 ⁇ 10 ⁇ 6 , respectively).
- Non-activated Iridium catalyst prepared in the previous studies [IrCl(cod)(IMes), 10 mg, 0.015 mmol, MW ⁇ 640] was added to an Eppendorf tube followed by the addition of 0.6 mL of the corresponding pyridine analog.
- the Eppendorf tube was vortexed, and the homogeneous content of the tube was transferred via a glass pipette to a medium-walled NMR (5 mm medium wall precision (3.43 mm ID), NMR Sample Tube 9 in. long, Wilmad glass P/N 503-PS-9) tube equipped with the Teflon tube (0.25 in. OD, 3/16 in. ID) extension, which was approximately 7 cm long.
- the tube was attached to the previously described setup through a push-to-connect adapter.
- the samples with pyridine (Py) were prepared and activated in the same manner as described for the picolines and lutidines above except that four different catalyst loadings (10 mg, 13 mg, 20 mg and 40 mg) were used for natural abundance (n.a.) Py yielding the following final concentrations: ⁇ 45 mM, ⁇ 60 mM, ⁇ 90 mM and ⁇ 180 mM respectively.
- the solutions of 15 N-Py and perdeuterated (99.5% d) Py were prepared and activated in the same fashion as described above using 20 mg of the same Ir catalyst, and yielding ⁇ 90 mM final catalyst concentration.
- the sample solution was bubbled with para-H 2 (the period of bubbling, flow rate, and pressure were varied depending on the goal of the experiment) inside the magnetic shield (Lake Shore Cryotronics, P/N 4065). This was followed by a rapid sample transfer from the shield to Earth magnetic field followed by quenching the flow of para-H 2 and sample insertion in the bore of 9.4 T magnet and acquisition of 15 N NMR spectrum. In case of the 15 N T 1 measurements in the microTesla field of the magnetic shield, the para-H 2 flow was stopped while the sample remained in the shield before it was removed from the shield.
- the sample tube with activated catalyst and to-be-hyperpolarized substrate is placed in the fringe field of the magnet at 6 ⁇ 4 mT (calibrated with gauss meter), and parahydrogen is bubbled for about 20-30 seconds.
- the exponential build-up constant for 1 H SABRE is about 7.4 s, and 20-30 seconds of para-H 2 bubbling is sufficient to reach the steady-state level of 1 H hyperpolarization.
- a method of hyperpolarizing heteronuclei comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; and (b) applying a magnetic field to the mixture, wherein the magnetic field causes the matching of the resonance frequency of parahydrogen with the resonance frequency of the at least one hyperpolarizable heteronucleus, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus.
- Clause 4 The method of clause 1, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are different.
- Clause 8 The method of clause 1, wherein the magnetic field has a strength of about 0.1 to about 1 ⁇ T.
- Clause 9 The method of clause 1, wherein the at least one heteronucleus is selected from the group consisting of 13 C, 15 N, 19 F, 29 Si, 31 P, 2 H and 129 Xe.
- Clause 10 The method of clause 1, wherein the at least one heteronucleus is 15 N.
- Clause 11 The method of clause 1, wherein the mixture further comprises a solvent.
- Clause 13 The method of clause 1, wherein the catalyst is a heterogeneous catalyst.
- Clause 14 The method of clause 1, wherein the catalyst is a homogeneous catalyst.
- Clause 15 The method of clause 1, wherein the catalyst comprises a transition metal.
- Clause 16 The method of clause 15, wherein the transition metal is iridium.
- Clause 18 The method of clause 1, wherein the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- Clause 19 The method of clause 1, wherein the compound is isotopically enriched.
- Clause 20 The method of clause 1, wherein the compound is a contrast agent for an in vivo imaging technique.
- a method of obtaining an MRI image comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; (b) applying a magnetic field to the mixture, wherein the magnetic field causes the matching of the resonance frequency of parahydrogen with the resonance frequency of the at least one hyperpolarizable heteronucleus of the compound, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; and (c) performing an MRI measurement or MR spectroscopy on the compound.
- a method of in vivo pH sensing comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; wherein the compound has at least one pKa value of about 6 to about 9; (b) applying a magnetic field to the mixture, wherein the magnetic field causes the matching of the resonance frequency of parahydrogen with the resonance frequency of the at least one hyperpolarizable heteronucleus of the compound, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; (c) removing the catalyst from the mixture; and (d) performing an in vivo imaging measurement on the compound.
- a method of performing an NMR experiment comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; (b) applying a magnetic field to the mixture, wherein the magnetic field causes the matching of the resonance frequency of parahydrogen with the resonance frequency of the at least one hyperpolarizable heteronucleus, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; and (c) performing an NMR measurement on the compound.
- Clause 25 The method of clause 23, wherein the chemical structure of the compound provided in step (a) is the same as the chemical structure of the compound subject to the NMR experiment in step (c).
- Clause 26 The method of clause 23, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are within an order of magnitude of each other.
- Clause 27 The method of clause 23, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are different.
- Clause 28 The method of clause 23, wherein the NMR experiment produces at least one enhanced signal in the NMR spectrum of the compound.
- Clause 29 The method of clause 23, wherein the magnetic field has a strength of less than 50 ⁇ T.
- Clause 30 The method of clause 23, wherein the magnetic field has a strength of less than 20 ⁇ T.
- Clause 31 The method of clause 23, wherein the magnetic field has a strength of less than 5 ⁇ T.
- Clause 32 The method of clause 23, wherein the magnetic field has a strength of about 0.1 to about 1 ⁇ T.
- Clause 33 The method of clause 23, wherein the at least one hyperpolarizable heteronucleus is selected from the group consisting of 13 C, 15 N, 19 F, 29 Si, 31 P, 2 H and 129 Xe.
- Clause 34 The method of clause 23, wherein the at least one hyperpolarizable heteronucleus is 15 N.
- Clause 35 The method of clause 23, wherein the mixture further comprises a solvent.
- Clause 36 The method of clause 35, wherein the solvent is a deuterated solvent.
- Clause 37 The method of clause 23, wherein the catalyst is a heterogeneous catalyst.
- Clause 38 The method of clause 23, wherein the catalyst is a homogeneous catalyst.
- Clause 39 The method of clause 23, wherein the catalyst comprises a transition metal.
- Clause 40 The method of clause 39, wherein the transition metal is iridium.
- Clause 42 The method of clause 23, wherein the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- Clause 43 The method of clause 23, wherein the compound is isotopically enriched.
- Clause 44 The method of clause 23, wherein the compound is a contrast agent for an in vivo imaging technique.
- a method of performing an NMR experiment comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; (b) applying a magnetic field with a strength of less than 50 ⁇ T to the mixture, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; and (c) performing an NMR measurement on the compound.
- Clause 47 The method of clause 45, wherein the chemical structure of the compound provided in step (a) is the same as the chemical structure of the compound subject to the NMR experiment in step (c).
- Clause 48 The method of clause 45, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are within an order of magnitude of each other.
- Clause 49 The method of clause 45, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are different.
- Clause 50 The method of clause 45, wherein the magnetic field is determined by matching the resonance frequency of parahydrogen with the resonance frequency of the at least one hyperpolarizable nucleus of the compound.
- Clause 51 The method of clause 45, wherein the NMR experiment produces at least one enhanced signal in the NMR spectrum of the compound.
- Clause 54 The method of clause 45, wherein the magnetic field has a strength of about 0.1 to about 1 ⁇ T.
- Clause 55 The method of clause 45, wherein the at least one heteronucleus is selected from the group consisting of 13 C, 15 N, 19 F, 29 Si, 31 P, 2H and 129 Xe.
- Clause 56 The method of clause 45, wherein the at least one heteronucleus is 15 N.
- Clause 57 The method of clause 45, wherein the mixture further comprises a solvent.
- Clause 58 The method of clause 57, wherein the solvent is a deuterated solvent.
- Clause 59 The method of clause 45, wherein the catalyst is a heterogeneous catalyst.
- Clause 60 The method of clause 45, wherein the catalyst is a homogeneous catalyst.
- Clause 61 The method of clause 45, wherein the catalyst comprises a transition metal.
- Clause 62 The method of clause 61, wherein the transition metal is iridium.
- Clause 64 The method of clause 45, wherein the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- Clause 65 The method of clause 45, wherein the compound is isotopically enriched.
- Clause 66 The method of clause 45, wherein the compound is a contrast agent for an in vivo imaging technique.
- a method of hyperpolarizing heteronuclei comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; and (b) applying a magnetic field with a strength of less than 50 T to the mixture, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus.
- Clause 69 The method of clause 67, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are within an order of magnitude of each other.
- Clause 70 The method of clause 67, wherein the resonance frequencies of parahydrogen and the at least one hyperpolarizable heteronucleus are different.
- Clause 71 The method of clause 67, wherein the magnetic field is determined by matching the resonance frequency of parahydrogen with the resonance frequency of at least one hyperpolarizable nucleus of the compound.
- Clause 72 The method of clause 67, wherein the magnetic field has a strength of less than 20 ⁇ T.
- Clause 74 The method of clause 67, wherein the magnetic field has a strength of about 0.1 to about 1 ⁇ T.
- Clause 75 The method of clause 67, wherein the at least one heteronucleus is selected from the group consisting of 13 C, 15 N, 19 F, 29 Si, 31 P, 2 H and 129 Xe.
- Clause 76 The method of clause 67, wherein the at least one heteronucleus is 15 N.
- Clause 77 The method of clause 67, wherein the mixture further comprises a solvent.
- Clause 78 The method of clause 77, wherein the solvent is a deuterated solvent.
- Clause 79 The method of clause 67, wherein the catalyst is a heterogeneous catalyst.
- Clause 80 The method of clause 67, wherein the catalyst is a homogeneous catalyst.
- Clause 81 The method of clause 67, wherein the catalyst comprises a transition metal.
- Clause 82 The method of clause 81, wherein the transition metal is iridium.
- Clause 84 The method of clause 67, wherein the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- the catalyst is a homogeneous or heterogeneous catalyst, wherein the catalyst accommodates the simultaneous exchange of para-H 2 and heteronuclear spin center(s), and wherein the condition of spin-spin (weak or strong J) coupling between para-H 2 derived protons and heteronuclear spin center(s) is maintained.
- Clause 85 The method of clause 67, wherein the compound is isotopically enriched.
- Clause 86 The method of clause 67, wherein the compound is a contrast agent for an in vivo imaging technique.
- a method of performing an NMR experiment comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; (b) applying a magnetic field with a strength of less than 50 ⁇ T to the mixture, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; and (c) performing an NMR measurement on the compound.
- Clause 88 The method of clause 87, wherein the NMR experiment produces at least one enhanced signal in the NMR spectrum of the compound.
- a method of obtaining an MRI image comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; (b) applying a magnetic field with a strength of less than 50 ⁇ T to the mixture, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; and (c) performing an MRI measurement or MR spectroscopy on the compound.
- a method of in vivo pH sensing comprising: (a) combining parahydrogen, a compound comprising at least one hyperpolarizable heteronucleus, and a catalyst to form a mixture; wherein the compound has at least one pKa value of about 6 to about 9; (b) applying a magnetic field with a strength of less than 50 ⁇ T to the mixture, thereby transferring the spin order from parahydrogen to the at least one hyperpolarizable heteronucleus; (c) removing the catalyst from the mixture; and (d) performing an in vivo imaging measurement on the compound.
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Abstract
Description
Δv HN =|J HH +J NN−(J HN +J HN′)/2| (1)
Δv HN =|J HH −J NN| (2)
where ΔvHN=vH−vN is the frequency difference between Ir-hydride protons and catalyst-bound 15N, and the J-couplings are as depicted in
H=v A(I Az +I′ Az)+v B(I Bz +I′ Bz)+J AA ·I A I′ A +J BB ·I B I′ B +J AB·(I A I B +I′ A I′ B)+J′ AB·(I′ A I B +I A I′ B) (3)
where useful features include that populations are represented by real on-diagonal elements and the x-Hamiltonian is represented by real off-diagonal elements without contributions on the diagonal.
TABLE 1 |
Summary of Results with Natural Abundance (n.a.) |
Pyridine (Py), Py-d5, 15N—Py, and their mixtures |
15N | ortho- | ||||||
[15N] | 15N ε @ | effective | 15N T1 | [1H] | 1H ε @ | [catalyst] | |
(mM) | 9.4 T | T1 μT (s) | 9.4 T (s) | (mM) | 9.4 T | (mM) | |
1) Py (n.a.)b | ~45 | ~−2900 | 5.5(0.5) | 60.8(0.6) | ~25000 | ~−4.2 | ~90 |
2) Py-d5 (99.5% d) | ~45 | ~−850 | 2.2(0.1) | 74.3(2.9) | ~125 | ~−60 | ~90 |
3) 15N—Py | ~12500 | ~−33 | 10.2(1.1 | 66.8(0.5) | ~25000 | ~−0.3 | ~90 |
4) catalyst activated | ~2000 | ~−520 | 10.1(0.8) | 69.9(0.3) | ~4000 | ~−2.6 | ~90 |
with 15N—Py, then | |||||||
Py-d5 added | |||||||
5) catalyst activated | ~1800 | ~−400 | 15.1(2.3) | 73.2(0.3) | ~3600 | ~−2.7 | ~90 |
with Py-d5, then | |||||||
15N—Py is added | |||||||
6) catalyst activated | ~1800 | ~−450 | 9.9(1.1) | 70.0(0.3) | ~3600 | ~−1.0 | ~90 |
with 15N—Py, then in | |||||||
n.a. Py is added | |||||||
7) catalyst activated | ~1800 | ~−380 | 8.2(1.1) | 69.9(0.3) | ~3600 | ~−0.6 | ~90 |
with n.a. Py, then | |||||||
15N—Py is added | |||||||
bConducted with >90% para-H2, while the rest of the data is collected using 65-75% para-H2, resulting in ~30-40% lower signal enhancements compared with those shown in |
Δv HN =|J HH +J NN−(J HN +J HN′)/2| (6)
Δv HN =|J HH −J NN| (7)
Δv=|J HH−(J HN +J HN′)/4| (8)
Claims (21)
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WO2018209334A1 (en) * | 2017-05-12 | 2018-11-15 | Vanderbilt University | Method for creating hyperpolarization at microtesla magnetic fields |
GB201710677D0 (en) * | 2017-07-03 | 2017-08-16 | Univ York | Polorisation transfer via a second metal complex |
US10520561B2 (en) * | 2017-09-27 | 2019-12-31 | General Electric Company | System and method for hyperpolarizing a substance and quenching radicals therein |
WO2019089961A1 (en) * | 2017-11-03 | 2019-05-09 | The Regents Of The University Of California | Wide dynamic range magnetic field cycler and ultra portable optical nanodiamond hyperpolarizer |
US11796610B2 (en) | 2018-03-09 | 2023-10-24 | Duke University | Compositions as molecular tags for hyperpolarization NMR and magnetic resonance and methods of making and using same |
US11834416B2 (en) | 2018-11-29 | 2023-12-05 | Board Of Trustees Of Southern Illinois University | Cleavable agents |
US11571686B2 (en) | 2019-02-15 | 2023-02-07 | Board Of Trustees Of Southern Illinois University | Removal of homogeneous catalysts from NMR/MRI agents hyperpolarized via sabre or PHIP |
JP7311174B2 (en) * | 2019-08-06 | 2023-07-19 | 国立大学法人北海道大学 | Polarization transfer device |
CN111537540A (en) * | 2020-05-18 | 2020-08-14 | 中国科学院精密测量科学与技术创新研究院 | Para-hydrogen induced polarization device and method used in low magnetic field |
EP4140505A1 (en) * | 2021-08-26 | 2023-03-01 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Purified signal-enhanced contrast agents for magnetic resonance imaging |
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